The mortality rate beyond the first year of heart transplantation has not shown a significant improvement in the last two decades. We hypothesized that the failure to improve long-term outcomes may be related to the field's reliance on animal models of rejection that do not capture preexisting or concomitant health conditions present in the human transplant population. One example of a concomitant condition that could affect transplant outcome is hyperlipidemia, a comorbidity that develops in 95% of patients within 5 years. Hyperlipidemia leads to development of atherosclerosis primarily as a result of increased serum cholesterol levels, however it is also now apparent that hyperlipidemia drives systemic inflammation in humans and mice by altering adaptive and innate immunity. We hypothesized that alterations in adaptive immunity resulting from hyperlipidemia may affect transplant outcome. To test this hypothesis we examined heart transplant rejection in hyperlipidemic mice. We observed that hyperlipidemia promotes rejection of allogeneic hearts transplants. Our data indicate that hyperlipidemia has a negative effect on regulatory T cells (Treg) function and alters the T cell subsets involved in rejection by promoting a strong Th17 component that is not observed in mice with normal lipid levels. Together these changes lead to resistance to tolerance induction using costimulatory molecule blockade. Thus, our data show that hyperlipidemia profoundly affects rejection responses and the ability to induce tolerance using clinically relevant strategies. Therefore it is critical to study rejection in the context of hyperlipidemia in order to develop novel strategies to improve outcomes. Our central goal is to develop a mechanistic understanding of how hyperlipidemia affects alloreactivity and transplant rejection by testing the hypothesis that hyperlipidemia alters adaptive alloimmune responses by changing the nature of the T cell subsets involved in rejection and by altering Tregs. Our specific aims are to: 1) Determine the mechanisms by which hyperlipidemia alters Treg subsets and function; 2) Determine the role of Th17 lineage cells in mediating rejection in hyperlipidemic mice and mechanisms that shape their response; and 3) Determine how hyperlipidemia promotes resistance to tolerance induction. These studies provide novel insight that will fundamentally change how we view transplant rejection and tolerance by revealing a previously unappreciated effect of hyperlipidemia on rejection, its regulation, and the ability to induce tolerance.